Results from the Cyclosporine A in Out-0f-Hospital Cardiac Arrest Resuscitation (CYRUS) trial corresponded with those of the recently published CIRCUS trial, in which administration of cyclosporine showed no benefit when given immediately after reperfusion injury in patients with acute myocardial infarction.

In the CYRUS study, treatment with 2.5 mg/kg IV bolus injection of cyclosporine given at the onset of advanced cardiovascular life support following cardiac arrest was not associated with a reduction in organ failure, as measured by Sequential Organ Failure Assessment (SOFA) score (median 10, interquartile range [IQR] 7-13 versus median 11, IQR 7-15 among controls), Laurent Argaud, MD, PhD, of Hospices Civils de Lyon, France, and colleagues reported online in JAMA Cardiology.

The researchers noted that therapeutic resumption of blood circulation, which is a primary therapeutic objective of cardiac resuscitation, is associated with risk for reperfusion injury and long-term injury.

"Opening of the mitochondrial permeability transition pore at the time of reperfusion has been reported to be involved in damage to various organs (e.g., heart, brain, liver, and kidney) after regional ischemia," Argaud's group wrote. "Experimental evidence suggests that, through mitochondrial determinants, reperfusion injury might also contribute to multiple organ failure following a global ischemic insult, including post-cardiac arrest syndrome."

Cyclosporine has been shown to prevent permeability transition pore opening early in reflow, and in early studies by Argaud's group and others, administration of the drug showed efficacy for preventing organ failure in nonshockable cardiac arrest.

In CYRUS, the researchers screened 6,758 nonshockable, out-of-hospital cardiac arrest (OHCA) patients treated at 16 ICUs at seven university-affiliated hospitals and nine general hospitals in France. A total of 794 of the patients were included in the intention-to-treat analysis (cyclosporine, n=400; control, n=394).

Among the main findings:

Twenty-four hours after hospital admission, SOFA scores were not significantly different among the cyclosporine (median, 10.0; IQR, 7.0-13.0) and the control (median, 11.0; IQR, 7.0-15.0) groups.

Survival was not significantly different between the cyclosporine and control patients (24.5% vs 25.6%) at hospital admission (adjusted odds ratio [aOR] 0.94, 95% CI 0.66-1.34).

While the study failed, the researchers suggested that "further studies are need to investigate other approaches to prevent resuscitation injury in the future."

In an editorial published with the study, Lance Becker, MD, and Peter Berger, MD, of Hofstra Northwell School of Medicine in Manhasset, N.Y., wrote that, while the 8 minute average time from life support team arrival to cyclosporine administration in the CYRUS trial was a commendable feat, it may not have been short enough to achieve a benefit in these critically-ill patients.

"Patients received the study drug an average of 27 minutes after collapse, which the authors cite as the most likely reason for their negative findings," they wrote. "While that may well be true, it is hard to image that this can be substantially improved in our current level of emergency medical system capabilities."

Becker and Berger also noted that the low dose of cyclosporine A used in the current study may have also contributed to the negative findings, and that, like cancer and HIV, optimal treatment to prevent reperfusion injury in this setting may involve multiple drugs.

"Several investigators have suggested that perhaps an anti-reperfusion injury 'cocktail' consisting of a combination of agents would be more successful than our current approach," they wrote, adding that therapeutic hypothermia, which is widely considered to be the most effective therapy for cardiac arrest, "acts (like a cocktail) on multiple biological pathways."

"Overall, we believe that the evidence suggests that reperfusion injury will require multiple agent therapies for effective treatment," they wrote.

Funding for this research was provided by the French Ministry of Health.

The researchers declared no relevant relationships with industry related to this study.

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